Thromboembolic disease (Proceedings)

Pathophysiology of thromboembolic disease

Thrombophilia (hypercoagulability or prothrombotic state) is a complex disorder with a diverse and multifactorial pathogenesis that results in a wide spectrum of clinical manifestations. It is well-recognized as a frequent and serious cause of morbidity and mortality in people. It appears less prevalent in dogs and cats for several reasons.

     • Deep vein thrombosis (DVT), the most common preceding event to pulmonary embolism (PE) in people, has yet to be documented in veterinary medicine.

     • Atherosclerosis, the most common cause of human arterial thrombosis, is uncommon in dogs. However hypothyroid and diabetic dogs have increased incidence of atherosclerotic lesions.

     • Multiple inherited thrombophilic disorders (protein C, protein S, or AT deficiency, activated protein C resistance) of people have yet to be reported in dogs or cats.

     • There are numerous risk factors in people (e.g. oral contraceptive therapy, pregnancy, smoking, elevated factor VIII or XI levels) that are not present in veterinary medicine.

Veterinary medicine

In veterinary medicine thrombophilia is becoming recognized more frequently in our patients. Numerous diseases have been associated with risk of thromboembolism (TE), but the actual incidence of thrombosis remains unclear; incidence data on PTE from postmortem reports identified rates of 0.9% in dogs and 0.06% in cats. While the hypercoagulable states are associated with an increased thrombotic risk, the actual formation of a thrombus is inconsistent, and the incidence variable. This inconsistency together with the difficultly in accurate antemortem diagnosis of TE, causes predicting TE complications exceedingly difficult, the need for prophylaxis unclear. Further, the efficacy of prophylaxis in veterinary medicine will be extremely challenging to verify. Numerous conditions have been associated with TE disease in veterinary medicine. They include IMHA, sepsis, neoplasia, cardiac disease (HW, cardiomyopathy, endocarditis), hypercorticolism, DIC, amyloidosis, glomerular disease, pancreatitis, intravenous catheters, trauma, recent surgery, cytotoxic drugs, blood transfusions, hypothyroidism, Blastomycosis, and total hip implants in dogs.Frequently patients will have more than one condition. In 2 retrospective studies of canine PTE, 59% and 64% of dogs had more than one disease process. The majority of patients had evidence of thrombosis in other organ systems. In cats the list of associated diseases includes cardiomyopathy, neoplasia, pancreatitis, IMHA, glomerular disease, protein losing enteropathy, steroid administration, sepsis, hepatic lipidosis, FIP, pneumonia, encephalitis, and HW

Clinical signs of a TE will obviously depend on location occlusion, if the occlusion is partial or complete, collateral blood supply and organ reserve. Diagnosing TE can prove challenging. Without a high index of suspicion, many go unrecognized. Of 16 cats, PTE was not a differential for any. While of 29 dogs, 17 had tachypnea/labored respiration, and in 10/17 PTE was suspected.2 In another report, only 2 of 47 cases with PTE was it considered a differential antemortem.

Diagnosis

Once the clinician is suspicious for TE disease, their diagnostic armamentarium is limited. The D-dimer assay, although sensitive for crosslinked fibrin, is not specific for a TE. False positives can occur following surgery, trauma, with SIRS, cases of hemoabdomen, and liver disease, and false negatives have been reported with aged or small thrombi. Diagnostic imaging (abdominal ultrasound, echocardiography, CT, MR, or pulmonary scintigraphy) should be the main focus for investigating and confirming TE. A new modality, thromboelastography (TEG), may allow more objective assessment of hypercoagulable states, but does not confirm the presence of a TE.

Therapy

Treating a TE can prove equally challenging. Although their use might be appealing, thrombolytic therapy can have devastating consequences. We should consider use of these drugs in people; the major indication being myocardial infarction, peripheral artery occlusion, DVT, and stroke. These conditions are rarely identified in veterinary medicine. Contraindications should be heeded – Absolute: active internal hemorrhage, intracranial neoplasia, head trauma, pregnancy, aortic dissection, hypertension, trauma or surgery with potential hemorrhage; and Relative: historic CPR, trauma or surgery within 2 weeks, history of hypertension, bleeding diathesis or anticoagulant use. A recent metanalysis could not conclude that thrombolytic therapy was better than heparin for PE in people. Heparin is infused simultaneously with t-PA for the treatment of myocardial infarction; for other conditions it is initiated following thrombolytic therapy.

The veterinary experience with these agents has been spotty, and less than encouraging.

SK

Ramsey reported streptokinase (SK) use in 8 cats with naturally occurring aortic thromboembolism (ATE), they all died suddenly during the maintenance infusion. In a more recent retrospective report of 46 cats with ATE treated with SK, 54% had return of pulses within 24 hours, and 33% were discharged from the hospital. Complications occurred sporadically including hemorrhage requiring transfusion, reperfusion injury (hyperkalemia, acidosis), respiratory distress, and neurologic signs. Four dogs treated with SK for ATE all had clot dissolution (3 complete, 1 partial); however 2 dogs were treated 3 times, 1 dog twice, and 1 dog once. Dosages administered were 90,000 units/30 minutes followed by 45,000 U/hr. It is unlikely SK is commercially available at this time.

t-PA

Pion reports that 43% of cats with ATE survive therapy and were walking w/in 48 hours of t-PA.20 Two case reports each describe the use of t-PA in a dog. One had ATE, the other cranial caval thrombosis; one dog suffered hemorrhage and both required multiple treatments. Dosages ranged from 1.1 to 0.2 mg/kg as hourly boluses. t-PA is typically cost prohibitive; a 50 mg vial costs ~$1800.

UK

Whelan reported the use of UK in 12 cats with ATE. Four of 12 had improved pulses following therapy; 3/12 had hyperkalemia none of which had clinical improvement; overall 5/12 improved and were discharged.

Whelan also reported UK treatment in 4 dogs, 1 with PE, 3 with ATE. None showed clinical improvement; the dog with PE survived. One dog had hyperkalemia & acidosis. Hemorrhage was not reported in either abstract. UK protocol was 4400 U/kg over 10 minutes, followed by 4400 U/kg over 12 hours. A 250,000 unit vial costs ~$525, and typically treats a 10 pound cat.

Thrombectomy

Reimer reported the use of a rheolytic thrombectomy system in 6 cats with ATE. Successful dissolution occurred in ⅚, 1 died of hemorrhage during the procedure, 3 survived to discharge.

Thrombolytic Summary

Given the costs, variable response, and complications, therapy with thrombolytics does not appear wise in the majority of situations. Additionally Smith reported that 45% of cats with ATE treated with heparin and/or aspirin survived to discharge.

Prophylaxis

Background

It is important to recognize that heparin administration for prophylaxis and thrombosis are not the same in people. The classic heparin target with thrombosis is to prolong the PTT 1.5 to 2.5 times normal. An IV bolus followed by a heparin CRI (5-20 U/kg/hr) is preferred. Venous TE is the 3rd most common cardiovascular disease in people; 1/1000 individuals are affected each year and is strongly associated with life threatening PE. Because of this thromboprophylaxis is routine in many disease conditions. Recently there have been great strides to develop new medications for thromboprophylaxis that have wider therapeutic ranges and can be taken orally. Rates of DVT are 13-33% of ICU patients and up to 27% of deceased ICU patients have PE. Other rates of DVT are 19% of elective abdominal surgery, 50% of either major orthopedic surgery or major trauma, and 60-100% of those with spinal cord injury. The American College of Chest Physicians recommends LMWH or low dose UH administration to acutely ill medical patients admitted with CHF, severe respiratory disease, confined to a bed, and have one or more risk factors.

     => When should prophylaxis be considered in veterinary medicine?

          • Opinion: Anticoagulant therapy should be considered in high risk patients with multiple risk factors (e.g. – a dog with proteinuria, receiving prednisone for allergies, who suffered significant trauma, and has multiple IVC).

Heparins – UH & LMWH

Heparin is affordable and readily available; however there is great individual variability in dose responsiveness. Of note, heparin not only effects AT, but also activates t-PA and inhibits platelet function. In recent years low molecular weight heparins (LMWH) (e.g., dalteparin or Fragmin® and enoxaprin or Lovenox®) have replaced unfractionated heparin (UH) in the acute and chronic management of PE and DVT in people; their mean molecular weight is 5 kDa versus 15 kDa of UH. The advantages of LWMH include improved bioavailability, prolonged half-life, predictable pharmacodynamics, and renal clearance. Their activity is via binding with AT and greater affinity for factor Xa, not thrombin. This is due to their shorter glycosaminoglycan sequence; LMWHs have a decreased ability to form a terniary complex with AT & thrombin. Hence monitoring is often not required; although when needed, LMWH are monitored by their amount of factor Xa activity inhibition (aka: anti-Xa activity). LMWH cost more that UH. Unfortunately their prolonged half-life in people does not occur in dogs and cats. Reported dosages and results vary. Initial reported effective doses in cats were 100 U/kg twice; a recent report suggested 180 U/kg four times daily for dalteparin. The same report suggested a feline dose of 1.25 mg/kg enoxaparin four times daily to maintain target anti-Xa activity of 0.5-1.0 IU/mL. Reports in dogs suggest similar frequent dosing is required: 0.8 mg/kg enoxaparin four times daily. Dalteparin dosed at 150 U/kg twice daily resulted in subtherapeutic anti-Xa activity at 12 hours. These target anti-Xa levels are adopted, and indicated for acute treatment of PE or DVT. An important observation is that 5000 units UH q8-12h is effective in decreasing fatal PE by ⅔ in people (extrapolated dosage ~ 62 U/kg UH).

References available upon request.